Objective: Widespread adoption of direct oral anticoagulants (DOACs) for atrial fibrillation and venous thromboembolism treatment has resulted in peripheral bypass patients receiving therapeutic anticoagulation with DOACs postoperatively. This study was undertaken to evaluate patient outcomes after open peripheral bypass based on anticoagulation treatment. Methods: Postoperative treatment and outcomes of patients undergoing peripheral bypass operations between January 2012 and December 2017 from a statewide multicenter quality improvement registry were examined. Surgeons participating in the registry were surveyed on practice patterns regarding DOACs in bypass patients. Multivariate logistic regression was performed for 30-day transfusion outcomes, and multiple linear regression was performed for length of stay. Results: Among 9682 patients, 7685 patients received no anticoagulation, whereas 1379 received a vitamin K antagonist (VKA) and 618 received a DOAC postoperatively. Patients receiving anticoagulation compared with no anticoagulation had a higher body mass index and were more likely to have preoperative anemia, congestive heart failure, and atrial fibrillation (all P < .001). Compared with patients receiving VKAs, patients receiving DOACs were less likely to have chronic kidney disease (P = .002) and more likely to have atrial fibrillation (P < .001). The shortest length of stay was among patients receiving no anticoagulation (median, 5 days; interquartile range, 3-9 days; P < .001), followed by DOACs (median, 6 days; interquartile range 3-11 days; P < .001) and VKAs (median, 8 days; interquartile range, 5-13 days; P < .001). Compared with patients receiving VKAs postoperatively, there was no difference in readmission for anticoagulation complications, bypass thrombectomy or thrombolysis, major amputation, or graft patency at 1 year among patients receiving DOACs. On multivariate logistic regression, patients receiving a DOAC (odds ratio, 0.743; confidence interval, 0.59-0.94; P = .011) or no anticoagulation (odds ratio, 0.792; confidence interval, 0.69-0.91; P = .001) were less likely to require transfusion within 30 days than patients taking VKAs. Approximately 70% of the surveyed surgeons reported that they “sometimes” or “always” use DOACs instead of VKAs for protection of a high-risk bypass. Conclusions: Among patients undergoing lower extremity surgical bypass, those receiving a DOAC postoperatively had a shorter length of stay and were less likely to receive a transfusion in 30 days without compromising graft patency and readmission for anticoagulation complications, thrombectomy, or thrombolysis or affecting amputation rate compared with those receiving a VKA. A majority of surgeons within the quality collaborative have adopted the use of DOACs after peripheral bypass, suggesting the need for a prospective trial evaluating DOAC safety and efficacy in patients requiring anticoagulation for high-risk bypass grafts.